Small-Molecule Disruption of the Myb/p300 Cooperation Targets Acute Myeloid Leukemia Cells
Small-Molecule Disruption of the Myb/p300 Cooperation Targets Acute Myeloid Leukemia Cells
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DOI：
10.1158/1535-7163.mct-16-0185
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发表时间：
2016-10
影响因子：
5.7
通讯作者：
S. Uttarkar;T. Piontek;S. Dukare;C. Schomburg;P. Schlenke;W. Berdel;C. Müller-Tidow;T. Schmidt;K. Klempnauer
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文献类型：
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作者：
S. Uttarkar;T. Piontek;S. Dukare;C. Schomburg;P. Schlenke;W. Berdel;C. Müller-Tidow;T. Schmidt;K. Klempnauer
转录因子c-Myb对造血细胞的增殖是必不可少的，并与白血病和其他人类癌症的发生有关。因此，对Myb的药理抑制正在成为治疗这些疾病的潜在策略。通过使用Myb报告细胞系，我们已经确定白花蛇舌素和几种萘醌类化合物是有效的低分子Myb抑制剂。我们证明，这些化合物通过与c-Myb反式激活结构域结合并破坏c-Myb与辅活化子p300的合作来抑制c-Myb，辅活化子p300是Myb活性的主要驱动因素。萘醌诱导的c-Myb抑制Myb靶基因表达，并诱导髓系白血病细胞系HL60分化。我们证明，小鼠和人类原代急性髓系白血病细胞比正常造血祖细胞对萘醌诱导的克隆性增殖抑制更敏感。总体而言，我们的工作首次证明了萘醌作为小分子Myb抑制剂的潜力，它可能具有治疗白血病和其他由解除调节的Myb驱动的肿瘤的潜力。摩尔癌症治疗；15(12)；2905-15。
The transcription factor c-Myb is essential for the proliferation of hematopoietic cells and has been implicated in the development of leukemia and other human cancers. Pharmacologic inhibition of Myb is therefore emerging as a potential therapeutic strategy for these diseases. By using a Myb reporter cell line, we have identified plumbagin and several naphthoquinones as potent low-molecular weight Myb inhibitors. We demonstrate that these compounds inhibit c-Myb by binding to the c-Myb transactivation domain and disrupting the cooperation of c-Myb with the coactivator p300, a major driver of Myb activity. Naphthoquinone-induced inhibition of c-Myb suppresses Myb target gene expression and induces the differentiation of the myeloid leukemia cell line HL60. We demonstrate that murine and human primary acute myeloid leukemia cells are more sensitive to naphthoquinone-induced inhibition of clonogenic proliferation than normal hematopoietic progenitor cells. Overall, our work demonstrates for the first time the potential of naphthoquinones as small-molecule Myb inhibitors that may have therapeutic potential for the treatment of leukemia and other tumors driven by deregulated Myb. Mol Cancer Ther; 15(12); 2905–15. ©2016 AACR.